Neural stem cells exist in the adult brain and continually generate new neurons, which respond to multiple physiological and pathological stimulations and are potentially involved in learning and memory, epilepsy, depression, and brain remodeling after injury. Most recent data also demonstrate an interconnection between neural stem cells and deadly brain tumors. The long-term goal of this application is to understand the regulation of adult neural stem cells and their roles under normal or diseased conditions. As integrators of multiple extracellular and intracellular signaling pathways and through direct interaction with the genome, transcription factors play key roles in cell type specification, proliferation, and differentiation. Our research will use one of these transcription factors as a molecular tool. We and others demonstrated that orphan nuclear receptor TLX (NR2E1) is absolutely required for the maintenance and proliferation of adult neural stem cells in neurogenic niches. We further showed that TLX-dependent adult neurogenesis contributes to spatial learning and memory. By employing the most advanced molecular, cellular and mouse genetic approaches, the studies described here seek to understand: 1) the transcriptional logic underlying the specification and maintenance of neural stem cells; and 2) the role of TLX-dependent neural stem cells in brain-related diseases. Results from this work will provide novel insights into our understanding of the biology of neural stem cells and their role under diseased conditions. Such knowledge will be pivotal to fulfill the promise of targeting these stem cells for therapeutics. PUBLIC HEALTH RELEVANCE: The existence of neural stem cells in the adult brain generates great hope for regenerative therapy for certain brain injuries, neurodegeneration, and depression. Concomitantly, these cells may be the cause and perpetuator of deadly brain tumors. Our proposed research will focus on understanding the regulation and function of adult neural stem cells under normal and disease conditions.